RESUMO
The effects of 5-azacytidine and hydroxyurea on their independent ability to change adult hemoglobin proportions toward newborn proportions in adult rats were examined. The results revealed that both the chemotherapeutic agents were capable of switching certain hemoglobin components toward newborn values and required similar time-span to express their actions. However, the switching effect of these drugs was totally lost if aspirin was simultaneously administered into the rats, reflecting the need for concurrent prostaglandin synthesis.
Assuntos
Aspirina/farmacologia , Azacitidina/antagonistas & inibidores , Hemoglobina Fetal/efeitos dos fármacos , Hidroxiureia/antagonistas & inibidores , Fatores Etários , Animais , Azacitidina/farmacologia , Hemoglobina Fetal/química , Hidroxiureia/farmacologia , Masculino , Ratos , Ratos Endogâmicos , Valores de ReferênciaRESUMO
The Salvador/Warts/Hippo (Hippo) signaling pathway defines a novel signaling cascade regulating cell contact inhibition, organ size control, cell growth, proliferation, apoptosis and cancer development in mammals. The upstream regulation of this pathway has been less well defined than the core kinase cassette. KIBRA has been shown to function as an upstream member of the Hippo pathway by influencing the phosphorylation of LATS and YAP, but functional consequences of these biochemical changes have not been previously addressed. We show that in MCF10A cells, loss of KIBRA expression displays epithelial-to-mesenchymal transition (EMT) features, which are concomitant with decreased LATS and YAP phosphorylation, but not MST1/2. In addition, ectopic KIBRA expression antagonizes YAP via the serine 127 phosphorylation site and we show that KIBRA, Willin and Merlin differentially regulate genes controlled by YAP. Finally, reduced KIBRA expression in primary breast cancer specimens correlates with the recently described claudin-low subtype, an aggressive sub-group with EMT features and a poor prognosis.
Assuntos
Transição Epitelial-Mesenquimal , Fator de Crescimento de Hepatócito/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Fatores de Transcrição/metabolismo , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Western Blotting , Mama/citologia , Mama/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Adesão Celular , Proteínas de Ciclo Celular , Movimento Celular , Proliferação de Células , Células Cultivadas , Claudina-1/genética , Claudina-1/metabolismo , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Feminino , Perfilação da Expressão Gênica , Fator de Crescimento de Hepatócito/antagonistas & inibidores , Fator de Crescimento de Hepatócito/genética , Humanos , Técnicas Imunoenzimáticas , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Neurofibromina 2/genética , Neurofibromina 2/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Análise de Sequência com Séries de Oligonucleotídeos , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/genética , Fosforilação , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Serina-Treonina Quinase 3 , Transdução de Sinais , Fatores de Transcrição/antagonistas & inibidoresRESUMO
Intratracheal administration of porcine pancreatic elastase (PPE) produced a dose related decline in lung function, as assessed by changes in dynamic lung compliance (C(dyn)) in New Zealand White rabbits. This occurred within 24 h of administration and persisted for 56 days (n=6). These lung function changes were accompanied by histological evidence of emphysema in the lungs and were not mimicked by intratracheal administration of the proteolytic enzyme trypsin. Neither the lung function nor the histological changes induced by elastase could be prevented or reversed by either the glucocorticosteroid, dexamethasone, or all trans retinoic acid (ATRA).Our data suggest that local administration of elastase to the lungs of rabbits may provide a convenient way to assess the effects of drugs on the changes induced by elastase in airways.